The endocannabinoid system consists of two G-protein coupled receptors, CB1 and CB2; their endogenous ligands like N-arachidonoyl ethanolamine (Anandamide, AEA) and 2-Archadanoyl glycerol (2-AG); the enzymes responsible for their biosynthesis and biodegradation (Fowler, C. J. et. al., Clin. Pharmacol, 2006, 20, 549-562; Pacher, P., et. al. Pharmacol. Rev., 2006, 58, 389-462). The amplitude and duration of action of fatty acid amides signaling are regulated in vivo mainly by a single degradative enzyme, fatty acid amide hydrolase (FAAH) (Cravatt, B. F. et. al., Nature, 1996, 384, 83). Fatty Acid Amide Hydrolase (FAAH) is an integral membrane protein belonging to a large class of enzymes known as amidase signature class (Chebrou, H. et. al. Biochim. Biophys. Acta., 1996, 1298, 285-293). FAAH knock-out data indicates that, selective inhibition of FAAH represents an attractive target for treatment of pain as well as other related indications without side effects caused by direct CB1 agonism.
Beside Anandamide and 2-AG, Δ9-tetrahydrocannabinol (THC, psychoactive ingredient of Marijuana) also activates CB1 and CB2. (Mechoulam, R. et. al. Boca Raton, Fla.: CRC Press). THC and other CB1 agonists have been recognized to possess beneficial therapeutic properties. However, these reagents also produce side effects including impairments in cognition, motor control that limit their broad clinical utility. Anandamide has been shown to possess cannabinoid-like analgesic properties and it is released by stimulated neurons. Elevated anadamide levels result in pain relief without motor and cognitive side effects. Supporting this, FAAH inhibitors that elevate anadamide levels have demonstrated efficacy in animal models of pain (Litchman, A. H., et. al. J. Pharmacol. Exp. Ther. 2004, 311, 441-448), inflammation (Jayamanne et. al., Br. J. Pharmacol., 2006, 147, 281-288), anxiety (Kathuria, S. et. al., Nat. Med. 2003, 9, 76-81), and depression (Piomelli, D., et. al., Proc. Natl. Acad. Sci. USA, 2005, 102, 18620-18625).
Several classes of Fatty Acid Amide Hydrolase (FAAH) inhibitors are known (Deng, H., et. al., Expert. Opion. Drug Discv., 2010, 5, 961-993). Based on mechanism of action, these inhibitors broadly can be classified as covalent irreversible inhibitors, covalent reversible inhibitors, noncovalent reversible inhibitors. Examples of α-ketoheterocycles (Boger, D. L., et. al. Proc. Natl. Acad. Sci. USA 2000, 97, 5044-5049; Leung, D. et. al., Nat. Biotechnol. 2003, 21, 687-691) belong to covalent reversible inhibitors. Series of N-Piperidine/N-piperazine carboxamides (Urea derivatives) (Ahn, K. et. al. Biochem, 2007, 46, 13019-13030; Ahn, K. et. al., Chem. Biol., 2009, 16, 411-420; Johnson, D. S., et. al., Bioorg. Med. Chem. Lett., 2009, 19, 2865-2869; Keith, J. M. et. al., Bioorg. Med. Chem. Lett., 2008, 18, 4838-4843), carbamates (Timmons, A., et. al. Bioorg. Med. Chem. Lett., 2008, 18, 2109-13; Tarzia, G. et. al., J. Med. Chem., 2003, 46, 2352-2360; Mor, M. et. al. J. Med. Chem., 2004, 47, 4998-5008) belong to covalent irreversible inhibitors. Examples of Ketobenzimidazoles (Min, X. et. al., Proc. Natl. Acad. Sci. USA, 2011, 108, 7379-7384) represent noncovalent reversible inhibitors.
International (PCT) publication number WO2009/127943 discloses piperidine based urea derivatives as fatty acid amide hydrolase inhibitors. International (PCT) publication number WO2006/054652 relates piperazine based urea derivatives as fatty acid amide hydrolase inhibitors for the treatment of sleep disorders, cerebrovascular disorders.
International (PCT) publication number WO2006/074025 discloses piperazinyl and piperidinyl ureas as modulators of fatty acid amide hydrolase.
There remains a need to find new compounds that are inhibitors of Fatty Acid Amide Hydrolase (FAAH) useful for the treatment of disease states mediated by Fatty Acid Amide Hydrolase (FAAH) including pain, inflammation.